Our most recent work has defined the mechanisms leading to the dominant negative effects of all but one (Y6D) of the many mutations in DSPP (discovered by this laboratory and by others) that cause all non-syndromic forms of Dentin Dysplasia (DD-II) and Dentinogenesis Imperfecta (DGI-II and III). The first class of mutations we discovered, loss of one or four DNA bases in the 2000 basepair 3' repeat domain (encoding 700 tandem copies of the nominal tripeptide, serine-serine-aspartic acid, SSD), causes the mutant DSPP protein to become very hydrophobic and, therefore, to be retained in the endoplasmic reticulum (ER). Mutant DSPP retained in the ER cause their dominant negative effects by then capturing the normal DSPP protein encoded by the patients' second (normal) allele (via calcium bridges), further decreasing the amount of DSPP secreted into the dentin matrix. We showed that the milder DD was likely caused by the subset of mutations in the DSPP proteins that were less effective at capturing the normal DSPP protein thereby permitting more of the normal allele's DSPP to be secreted into the dentin matrix. The second class of mutations are all in the beginning of the DSPP gene and ultimately result in changes in the first three amino acids of the mature DSPP protein. Mutations in this tripeptide (isoleucine-proline-valine, IPV) also result in inefficient trafficking of the defective DSPP out of the ER. In 2018 we showed that the Surf4 gene encodes the ER cargo receptor that binds to this starting tripeptide and enhances the trafficking of DSPP out of the cell. Furthermore, we have shown that Surf4 (known as Erv29p in yeast) binds to a variety of different secreted proteins including many acidic proteins, specific hormones and some enzymes via their starting tripeptides. The chemical composition of amino-terminal tripeptides (there are 8000 different possibilities) leads to differing binding affinities for Surf4/Erv29p and ultimately to different steady-state levels in the ER lumen. In contrast, proteins that should remain in the ER (e.g. chaperones and modifying enzymes) and proteins too large to fit into classic ER exit vesicles (e.g. fibrillar collagens) start with tripeptide motifs with no affinity for Surf4/ERV29p so they are not trafficked by this cargo receptor. We have named this this tripeptide motif, ER-Exit of Soluble Cargo using Amino-terminal Peptide-Encoding Motif (ER-ESCAPE Motif).